Rapid and effective wound closure remains an important goal of virtually all modern endoscopic and conventional surgical procedures. Additionally, surgical reconnection of injured tissues is essential for restoration of their structre and function. While, the discontinuity in soft tissues is traditionally secured with mechanical perforating devices (e.g., sutures, tacks, and staples), these devices are also a source of complications, such as tissue trauma, chronic pain and discomfort, and localized stress concentrations which can lead to failure of the repair. Tissue adhesives can potentially simplify complex procedures, reduce surgery time, and minimize trauma. However, due to stringent design requirements such as water-resistant adhesion, biocompatibility, and degradability, successful tissue adhesives have been difficult to engineer. Existing tissue adhesives are hampered by weak adhesive strength (i.e., fibrin glue) and poor biocompatibility (i.e., cyanoacrylate), which limit their potential applications in surgery. The long term goal of this project is to develop tissue adhesives with strong adhesive strength and biomechanical properties matching those of native tissue to repair tissues that routinely experience large, repeated loads (e.g., cartilage, tendon, and ligament). The objective of this proposal is to establish the feasibility that functionalizing biocompatible and tough hydrogel with marine adhesive moiety will lead to a novel bioadhesive with elevated adhesive strength. The central hypothesis of this proposal is that an optimal combination of elevated bulk material toughness with strong water-resistant interfacial binding strength will yield a tissue adhesive with superior adhesive properties (i.e., work of adhesion). The work to be accomplished in this proposal includes: 1) functionalize a tough hydrogel with water-resistant adhesive moiety and to investigate its adhesive properties and rate of degradation in vitro; 2) determine preliminary biocompatibility of the adhesive using in vitro cell culture and subcutaneous implantation in rat. The expected outcomes include a biocompatible tissue adhesive with significantly higher adhesive strength when compared to existing tissue adhesives. Successful completion of the proposed work will lead to follow-on projects aimed at incorporating other desirable physical and biological properties into the adhesive such as in situ curing (e.g., minimally invasive delivery and conformity to a tissue defect), in situ activation (e.g., activation upon contact with wetted tissue to minimize the need for complex preparation prior to use), bioactivity (e.g., cell binding, tissue in growth), and tailoring the adhesive to a specific application (e.g., tendon repair, cartilage repair, ligament repair, tissue engineering scaffold fixation, suture-less anastomosis of cardiovascular or bowel tissues, drug delivery, etc.). This AREA award will provide the PI with resources to train undergraduate and graduate students, obtain data for future NIH funding, and build a nationally-recognized graduate program.